There is mounting evidence to suggest that the initiation and development of atherosclerotic lesions are promoted by the oxidation of lipoproteins. We continue to test this theory and in this project pursue further the hypothesis that the lipids formed during LDL oxidation damage vascular endothelial (EC) and smooth muscle cells (SMC) and change cell function in ways that promote atherosclerosis. We believe that identifying specific lipids of oxidized LDL (oxLDL) that inflict cell injury, determining the role of antioxidants in protecting cells, understanding the changes in cellular function caused by sublethal injury, and elucidating the mechanisms by which injury occurs, will lead to a clearer knowledge of the atherosclerotic disease process. This may, in turn, lead to novel ways to intervene in lesion progression. Our recent observations have heightened our interest in the cellular injuries caused by two specific lipids of oxLDL. 7beta-hydroperoxycholesterol (7beta-00Hchol) and lysophosphatidylcholine (lysoPC). Both compounds share the ability to inflict cell injury by inducing oxidative events. In Aim 1 we study the proliferative influences of oxLDL on SMC, which we have shown to be in large part due to a lysoPC-mediated, antioxidant-inhibitable release of basic fibroblast growth factor (FGF-2). We propose to define the mechanisms by which lysoPC causes FGF-2 release and promotes SMC proliferation. Aim 2 is based on our finds that 7beta-00Hchol is the dominant toxin among oxLDL lipids, that it injures cells by inducing peroxidation of cell lipids and that vitamin E protects against this injury. We will study the metabolism of 7beta-00Hchol by EC and the ability of the enzyme phospholipid hydroperoxide glutathione peroxidase (PHGPx), which reduces complex lipid hydroperoxides, to protect cells from 7beta-00Hchol-induced injury. In Aim 3 we take steps toward understanding the relevance of these phenomena in vivo. We propose to make a transgenic mouse that over expresses PHGPx and breed this mouse to the apoE knockout mouse model of atherosclerosis. We wish to test the prophylactic effects of reducing cellular lipid hydroperoxides on atherosclerosis progression.